Childhood Exposure to Excess Ionizing Radiation Is Associated with Dose-Dependent Fusions as Molecular Drivers of Papillary Thyroid Cancer.

Abstract

Exposure to excess ionizing radiation has been identified as a risk factor for the development of thyroid cancer (1). However, there are no well-established biomarkers indicating exposure to radiation as the etiology of thyroid tumors that can be applied in clinical care or in legal claims. Morton et al. analyzed a large cohort of individuals who were exposed to a power plant accident in Chernobyl in 1986 in their childhood and who subsequently developed papillary thyroid cancer (PTC) (2). The goal of the study was to enhance our understanding of radiation-induced carcinogenesis based on assessment of the molecular drivers, transcriptomics, and epigenetic profile of PTC associated with excessive environmental radiation exposure. The authors performed whole-genome sequencing, single-nucleotide polymorphism (SNP) microarray genotyping, mRNA and microRNA sequencing, methylation profiling, transcriptome analysis, and telomere-length quantification in 440 pathologically confirmed fresh-frozen PTC tissue samples for which matched normal tissue from either nontumor thyroid and/or blood was available. In the study group, 359 subjects were exposed to excess ionizing radiation in childhood or in utero; 81 individuals who were born more than 9 months after the Chernobyl accident served as a reference group. The data were analyzed adjusting for covariates that potentially affect PTC incidence, including sex, age at diagnosis, age at radiation exposure, and latency (defined as the time from exposure to PTC diagnosis). The median age at exposure to ionizing radiation was 7.3 years and the median latency before the diagnosis of PTC was 22.4 years. The exposure estimates (250 mGy on average and up to 8800 mGy) were based on direct measurements of the thyroid-absorbed dose within 8 weeks after the accident in 53 individuals, while for the remaining cohort, they were imputed from direct measurements in individuals living in a similar area.The molecular drivers were identified in the vast majority of the tumors (98.4%), mainly as a low mutation burden consisting of single candidates in the mitogen-activated protein kinase (MAPK) pathway. The most common driver was the BRAF V600E mutation, but fusions in RET proto-oncogene, receptor tyrosine kinase (RTK), such as NTRK1, NTRK3, ALK, as well as BRAF, PPRAG, and IGF2/IGF2BP3 accounted for the majority of the remaining drivers (41% of the tumors). Moreover, there was a significant association between fusion drivers and radiation dose, after adjustment for age at diagnosis and sex. Same significant association with radiation was observed for small deletions and balanced structural variants resulting from the nonhomologous end-joining repair of double-stranded DNA damage. In contrast, transcriptome, methylome, or telomere length were not significantly associated with the radiation dose, and all tumors were microsatellite-stable. No novel molecular signature unique for radiation-associated PTC has been identified. The study reveals potential mechanisms behind radiation-associated PTC, consisting of DNA double-stranded breaks leading to nonhomologous end-joining repair mechanisms, that result in pathogenic gene fusions responsible for clonal growth. There is no unique signature of radiation-associated PTC that could serve as a biomarker of radiation-induced malignancy.